The long range goal of this application is to understand the mechanisms by which estrogen and environmental estrogens affect hypothalamic functions such as energy homeostasis. There is an obesity epidemic in the US and understanding the etiology of any and all factors that contribute to expression of obesity is critical for treatment of this disorder. Therefore, the goal of the mentored projects is to understand how estradiol affects energy homeostasis through multiple membrane-initiated mechanisms that include the control of neuronal excitability through an estradiol-responsive membrane GPCR (mER) and control of gene expression in arcuate neurons through both ER?- and mER-mediated mechanisms. Estradiol is known to control energy homeostasis through ER? and mER because STX, a selective ligand for the mER, attenuates body weight gain post-ovariectomy. Estradiol also alters neuronal excitability of POMC arcuate neurons through the mER. One potential mER-mediated mechanism for the effects of estradiol is modulation of a non-inactivating, sub-threshold K+ current that tempers the excitability of POMC (M-current). To determine if modulation of the M-current by estradiol plays a role in these effects, I will first measure the expression and activity of the KCNQ/M-current in POMC and NPY neurons from oil- and estradiol-treated females using qRT-PCR in pooled single cells and electrophysiology. Second, I will measure the effects of acute (via mER) estradiol treatment on the electrophysiological properties of the M-current in POMC and NPY neurons using whole cell patch recordings. The independent phase will build on the techniques learned during the mentored phase and examine the role of membrane-initiated and ERE-independent estrogen signaling in hypothalamic functions and determine whether environmental estrogens activate these same pathways in their effects. The first aim will determine the role of ERE-independent signaling in the control of energy homeostasis and hypothalamic gene regulation by estradiol and bisphenol A using wild-type, ?ERKO and ERalpha KI/KO mice models. The final aim will determine the electrophysiological effects of bisphenol A on arcuate POMC and NPY neurons that control energy homeostasis. PUBLIC HEALTH RELEVANCE: The mentored phase may directly impact the health of women (esp. post-menopausal women) since STX, the selective ligand for the membrane estrogen receptor, is a potential lead compound for an non-traditional hormone replacement therapy and treatment of obsesity disorders. Finally, the independent phase will address the potential mechanisms that environmental estrogens can impact hypothalamic functions.